Type 2 diabetes mellitus (T2D) affects approximately 21 million individuals in the U.S., or almost 10% of the U.S. adult population. Because diabetes is determined by both genetic and environmental factors, a better understanding of the etiology of diabetes requires a careful investigation of gene-environment interactions. The Nurses? Health Study (NHS) and Health Professionals? Follow-up Study (HPFS) are well-characterized cohort studies of women and men for whom stored blood and DNA samples are available as well as detailed information on dietary and lifestyle variables. Using these unparalleled resources, our group has established an excellent track record of documenting important dietary, lifestyle, biochemical, and genetic risk factors for T2D. Thus, we are well-positioned to respond to the RFA ?Genome-wide association studies in the genes and environment initiative ? Study Investigators (U01)? (RFA-HG-06-033). The specific aims of this application include: 1. To conduct a GWA study among 3,000 cases of T2D and 3,000 healthy controls in NHS/HPFS cohorts. 2. To use information on the joint effects of genes and a list of carefully selected environmental exposures at the initial screening stage to test gene-environment interactions. This approach optimizes our power to detect variants that have a sizeable marginal effect and those with a small marginal effect but a sizeable effect in a stratum defined by an environmental exposure. To achieve this aim, we have developed a joint test of genetic marginal effect and gene-environment interaction. This flexible two-degree-of-freedom test generally provides greater power than standard methods and has the potential to uncover both marginal genetic effects and stratum-specific effects. To meet the data sharing requirement of the RFA, we plan to submit relevant dietary and lifestyle data to the National Center for Biotechnology Information (NCBI) on members of the nested case-control studies in the NHS/HPFS. One of the main strengths is the availability of comprehensive, validated environmental exposures in large well-characterized cohort studies for which stored blood and DNA samples are available. We believe that the unprecedented resources generated from this project will be extremely beneficial to the research community.